Misfolded, amyloid-like protein deposits in cells and tissues are commonly associated with numerous human diseases, including Alzheimer's disease (AD), prion diseases, Parkinson's disease, Type-II diabetes etc. representing tremendous medical, social and financial problems. The Alzheimer's disease involves the formation of extracellular fibrillar deposits of amyloid-beta (A2) peptide known as amyloid plaques (senile plaques). These fibrils (polymeric aggregates) and soluble oligomers of A2 peptide are associated with pathology. Accordingly, the inhibition of both seeding and self-assembly process of A2 is a promising therapeutic strategy. The principal goal of this proposal is to develop effective inhibitor compounds against the self-assembly of A2. As a continuation of our ongoing studies, we propose the synthesis of a broad variety of new compounds based on a core structure designed earlier. Our investigations have resulted in the identification of lead compounds and have also provided some indication of possible binding mechanism between the peptide and the inhibitors. In this proposal these prior results will be expanded upon and further work is proposed to perform a systematic synthetic study to create a large number of derivatives of the lead compounds. We will study the effect of these new inhibitor candidates on the self-assembly of the A2 peptide, including the formation of oligomers and fibrils. We intend to develop a broad structure-activity relationship scheme using a large set of structurally similar compounds. In a recent study we have observed that while the large number of reported inhibitors contain common structural motifs, these compounds are structurally diverse. It is our hypothesis that using a broad variety of inhibitors based on the same core structure we will describe a SAR that will be useful in classifying the crucial structural elements that an effective inhibitor should possess. We will test this hypothesis in this proposal with the ultimate goal to identify new effective inhibitors for A2 self- assembly. PUBLIC HEALTH RELEVANCE: Misfolded, amyloid-like protein deposits in cells and tissues are commonly associated with numerous human diseases, including Alzheimer's disease (AD). The principal goal of this proposal is to develop effective inhibitor compounds against the self-assembly of Alzheimer's amyloid beta peptide and contribute to the discovery of novel drug candidates against Alzheimer's disease and related amyloid disorders.